It is often assumed that bilayers in membranes have the thicknesses that they would have in vesicles made from the lipids alone. Many ideas rest on this view, including hydrophobicity scans to find helices, notions of protein sorting between membranes, and the rationale for the huge literature on pure lipids. Yet almost no measurements exist as points of reference for the thicknesses of actual membranes. Similarly, there are few data to inform us of the proportion of the area of a natural membrane that can be regarded as an unperturbed bilayer. Our preliminary studies suggest that the classical view, first established in the Fluid Mosaic Model, may be in need of revision: proteins rather than lipids set membrane dimensions. A consequence is that strain exists between protein and lipid, and the implications will be fascinating to explore. The principal themes of this proposal are to use diffraction to measure the mutual influences of membrane proteins, phospholipid and cholesterol on membrane thickness, to establish values for the areas .occupied by these components at the membrane center, and to use model systems that combine biochemistry and molecular dynamics simulations to discern the underlying chemical principles.